6-phenyl-4h-s-triazolo(4,3-a)(1,4)benzodiazepines and their production

ABSTRACT

1-SUBSTITUTED - 6 - PHENYL - 4H - S - TRIAZOLO(4,3-A)(1,4) BENZODIAZEPINES OF THE FORMULA VI:   1-R,4-R1,6-(R2,R3-PHENYL),R4,R5-4H-S-TRIAZOLO(4,3A)(1,4)   BENZODIAZEPINE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF CHLORINE, BROMINE, CYANO, OR&#39;&#39; IN WHICH THE ALKYL GROUP R&#39;&#39; IS OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND   -N(-R&#34;)(-R&#39;&#39;&#34;)   IN WHICH R&#34; AND R&#34;&#39;&#39; ARE ALKYL GROUPS DEFINED AS ABOVE OR TOGETHER   -N(-R&#39;&#39;)(-R&#34;)   REPRESENT PYRROLIDINO, PIPERIDINO, AND MORPHOLINO; WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL, AS DEFINED ABOVE; AND WHEREIN R2, R3, R4, AND R5 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL, AS DEFINED ABOVE, DIALKYLAMINE, IN WHICH ALKYL IS DEFINED AS ABOVE, FLUORO, CHLORO, BROMO, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKYLTHIO, ALKYLSULFINYL, AND ALKYLSULFONYL, IN WHICH THE CARBON CHAIN MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCLUSIVE, ARE PRODUCED BY HEATING A 4H-S-TRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE:   4-R1,6-(R2,R3-PHENYL),R4,R5-4H-S-TRIAZOLO(4,3A)(1,4)   BENZODIAZEPINE   WHEREIN R1, R2, R3, R4, AND R5 ARE DEFINED AS ABOVE, WITH A N-HALOSUCCINIMIDE (CHLORO OR BROMO) TO GIVE THE COMPOUND II (OR VI IN WHICH R IS CHLORINE OR BROMINE). THE COMPOUND IIA (R OF VI IS BROMO) GIVES WITH CUPROUS CYANIDE THE COMPOUND III (R = CN), WITH SODIUM ALKOXIDE IV (R=OR&#39;&#39; R&#39;&#39; DEFINED AS ABOVE); AND WITH A SECONDARY AMINE THE COMPOUND V   -N(-R&#34;)(-R&#39;&#39;&#34;)   IN WHICH R&#34; AD R&#34;&#39;&#39; ARE ALKYL, DEFINED AS ABOVE OR   -N(-R&#39;&#39;)(-R&#34;)   ARE PYRROLIDINO, PIPERIDINO AND MORPHOLINO. THE NEW PRODUCTS OF FORMULA VI INCLUDING THEIR PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS ARE USEFUL AS SEDATIVES, TRANSQUILLIZERS, AND MUSCLE RELAXANTS IN MAMMALS AND BIRDS.

United States Patent 3,709,899 G-PHENYL-4H-s-TRIAZOLO[4,3-a][I,4]BENZODI- AZEPINES AND THEIR PRODUCTION Jackson B. Hester, Jr., Galesburg, Mich., assignor to The Upjohn Company, Kalamazoo, Mich.

No Drawing. Filed Apr. 28, 1971, Ser. No. 138,291 Int. Cl. C07d 57/02 US. Cl. 260-308 R 19 Claims ABSTRACT OF THE DISCLOSURE l-substituted 6 phenyl 4H s triazolo[4,3-a] [1,4] benzodiazepines of the Formula VI:

wherein R is selected from the group consisting of chlorine, bromine, cyano, OR in which the alkyl group R is of 1 to 3 carbon atoms, inclusive, and

in which R" and R' are alkyl groups defined as above or together 1 to 3 carbon atoms, inclusive, are produced by heating a 4H-s-triazolo[4,3-a] [1,4]benzodiazepine:

wherein R R R R and R are defined as above, with a N-halosuccinimide (chloro or bromo) to give the compound II (or VI in which R is chlorine or bromine). The compound Ila (R of V1 is bromo) gives with cuprous cyanide the compound III (R=CN), with sodium alkoxide 3,709,899 Patented Jan. 9, 1973 "Ice IV (R=OR R defined as above); and with a secondary amine the compound V in which R" and R' are alkyl, defined as above or \RIII are pyrrolidino, piperidino and morpholino.

The new products of Formula VI including their pharmacologically acceptable acid addition salts are useful as sedatives, transquillizers, and muscle relaxants in mammals and birds.

BACKGOUND OF THE INVENTION Field of the invention This invention is directed to new organic compounds and is particularly concerned with novel 1-substituted-6- phenyl 4H s triazolo [4,3-a] [1,4]benzodiazepines and a process for the production thereof.

The novel compounds and the process of production therefor can be illustratively represented as follows:

wherein R is alkyl of 1 to 3 carbon atoms, inclusive, wherein R is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, inclusive; wherein R R R and R are selected from the group consisting of hydrogen, alkyl, as defined above, fluoro, chloro, bromo, nitro, cyano, trifiuoromethyl, and alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of l to 3 carbon atoms, inclusive; wherein X is chlorine or bromine; wherein R and R are alkyl, defined as above, or together are pyrroiidino, piperidino, and morpholino.

The new compounds 11 Ha, III, IV, and V which can be summarily, illustratively represented by the Formula VI: I

wherein R is selected from the group consisting of chlorine, bromine, cyano, OR, in which R is an alkyl group of 1 to 3 carbon atoms, inclusive and in which R", and R are alkyl defined as above, or together RIII are pyrrolidino, piperidino, and morpholino; wherein R is selected from the group consisting of hydrogen and alkyl, as defined above; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl as defined above, chloro, fiuoro, bromo, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive. The process of this invention comprises:

(1) Heating at 40 76 C. a selected 6-phenyl-4H-striazolo[4,3-a] [1,41benzodiazepine (I) with a N-chloroor N-bromosuccinimide in an inert, organic solvent, to give the corresponding l-chloroor l-bromo-G-phenyl- 4H-s-triazolo[4,3-a][1,4]benzodiazepine (II): (1) heating preferably Ila [the l-substituent in Ha is bromo; but the chloro compound is also operable] in an inert, organic, high boiling solvent at 120-170 to obtain the corresponding l-cyano 6 phenyl 4H s triazolo[4,3-a]- [1,41benzodiazepine III; or (2) heating IIa at 60-97" C. with a sodium or potassium lower alkoxide of formula R'O wherein R is alkyl of 1 to 3 carbon atoms, inclusive, in an excess of lower alkanol R'OH in which R is defined as above, to obtain the corresponding 1-alkoxy-6- phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (IV); or (3) heating IIa with a dialkylamine, pyrrolidine, piperidine, or morpholine, alkyl or one to three carbon atoms, inclusive, to give the corresponding l-(substituted amino)- G-phenyl 4H s triazolo [4,3-a] [1,4]benzodiazepine V.

DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkyl groups of I to 3 carbon atoms, inclusive,

are exemplified by methyl, ethyl, propyl, and isopropyl.

The carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino is alkyl of 1 to 3 carbon atoms, inclusive, as above.

The novel compounds of the Formula VI including acid addition salts thereof have sedative, tranquilizing and muscle relaxant effect in mammals and birds.

The acid addition salts of compounds of Formula VI contemplated in this invention, are the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates, and the like, prepared by reacting a compound of Formula V1 with an excess of the selected pharmacologically acceptable acid.

Sedative elfects of 1,8-dichloro 6 phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine are shown by the following tests in mice:

Chimney test.[Med. Exp. 4, 11 (1961)]: The eifective intraperitoneal dosage for 50% of mice (ED is 1.6 mg./kg. The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the elfective dosage, 50% of the mice failed doing it.

Dish test-Mice in Petri dishes (10 cm. diameter, 5 cm. high, partially embedded in wood shavings), climb out in a very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicates tranqnilization. ED equals the dose of test compound at which 50% of the mice remain in the dish. The ED (intraperitoneal administration) in this test was 1.0 mg./ kg.

Pedestal test.-The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute. The ED (intraperitoneal administration) was 1.1 mg./ kg.

Nicotine antagonism test.Mice in a group of 6 are injected with the test compound (1,8-dichloro-6-phenyl-4H- s triazolo[4,3-a][1,41benzodiazepine). Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show overstimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits; followed by (3) death. An intraperitoneal dosage of 0.71 mg./kg. of the test compound protected 50% of the mice against (2) and 0.8 mg./kg. against (3).

Antagonism to strychnine (as sulfate).-The effective dosage (ED of 1,8-dichloro-6-phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine is 7 mg./kg. orally in mice. The test consists in orally administering to groups of 6 mice the test compound, l,8-dichloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 30 minutes later 3 mgJkg. strychnine sulfate intraperitoneally. The survivors after 4 hours reflect the activity of the compound as a muscle relaxant and antispasmodic. A dosage of 3 mgJkg. of strychnine sulfate is routinely fatal to all the control mice.

The following compounds have (by intraperitoneal injection) ED as shown in the table below:

59 g-l J Compound Ch D P Ni 1bromo-8chlor0-6-phenyl-4H-s-triazolo[4,3-a]- [1,41benz0dlazeplne 8 9 10 1. 4 1-cyano-8-chloro-6-phenyltfl-s-triazoloifi- [1 ,41benzodiazepine 2. 2 2. 5 5. 0 0. 7

[1,41benzcdiazep e 0.1 0.08 0.18 0.045

preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added.

For mammals and birds, food premixes with starch, oatmeal, dried flshmeat, fishmeal, flour and the like can be prepared.

As tranquilizer the compounds of Formula VI can be used in dosages of 0.1 to 25 mg./kg. in oral or injectable preparations as described above, to alleviate tension and anxiety in mammals, or birds, such as e.g., occurs when animals are in travel.

Other acid addition salts of the compounds of Formula VI can be made such as the fluosilicic acid addition salts which are useful mothproofing compounds or the trichloroacetates useful as herbicides against Johnson grass, Bermuda grass, yellow foxtail and green foxtail, and quack grass.

The starting materials of Formula I of this invention, are prepared as shown in Preparation 1.

In carrying out the process of this invention, a selected 6-phenyl 4H s-triazolo[4,3-a][1,4]benzodiazepine (I) is heated with a halogenating agent providing a chloro or bromo atom for the halogenation. Halogenating agents for this reaction are N-bromoand N-chloroacetamide and preferably N-chloroand N-bromo succinimide. The reaction is carried out in an inert organic solvent, e.g. methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride and the like at a temperature of 40-76 C., preferably at the reflux temperature of the mixture for a period of 2 to 8 hours. The product, thus obtained, a l-chloroor 1-bromo-6-phenyl 4H s-triazolo- [4,3-a][1,4]-benzodiazepine, (II) is recovered and purified by conventional procedures, e.g. extraction, chromatography, crystallization and the like.

Compound IIa, l-bromo 6 phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine i.e. a compound II in which the l-position is substituted with bromine, is converted to l-cyano 6 phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiaze pine (III) by heating it with cuprous cyanide in a highboiling organic solvent for 1 to hours between 120- 170 C. Solvents useful for this purpose are dimethylmethylacetamide, diethyl acetamide, xylenes, trimethylformamide, diethylformamide, dipropylformamide, dibenzenes and the like. After the reaction is terminated, the product HI is isolated and purified by conventional procedures, i.e. extraction, chromatography, crystallization, and the like.

1-alkoxy-6-phenyl 4H s triazolo[4,3-a] [1,4]benzodiazepines (IV) are produced from Compounds IIa by heating a selected Compound IIa with an alkali metal salt of an alkanol in an excess of the lower alkanol conveniently at reflux or between 60-97 C. for fifteen minutes to 2 hours. Useful alkoxides of this type are sodium and potassium methoxide, ethoxide, propoxide isopropoxide with a solvent of the same type, i.e. methanol, ethanol, and 1- and 2-propanol. At the termination, the mixtures is preferably poured into excess water and extracted with a water-immiscible solvent. The extracted products are purified by conventional procedures e.g. chromatography and crystallizations.

Compounds of Formula IIa can be reacted with an amine of the formula RI HN in which is defined as above, to give the corresponding 1-amino-6- phenyl-4H-s-triazolo[4,3 a][l,4]benzodiazepine V. This reaction is preferably carried out between 55100 C. with or without a solvent. As solvent ethanol, propanol, dioxane, tetrahydrofuran, dibutyl ether, hexamethylphosphoric acid amide, or the like can be used or just an excess of amine. Diethylamine, dipropylamine, di-isopropylamine can be used in this manner. For dimethylamine a solvent is used or sealed tube techniques are necessary, due to its low boiling point. The time of reaction is 1-18 hours. An alkali metal salt of the amine e.g. sodium dimethylamide in a solvent can be used in this reaction. After termination of the reaction, the product V is isolated and purified by conventional procedures, i.e. extractinn, chromatography, crystallization and the like.

The following preparations and examples are illustrative of the processes and products of the present in vention, but are not to be construed as limiting.

PREPARATION 1 8-chloro-6-pheny1-4H-s-triazolo [4,3-a] 1,4]-

benzodiazepine A solution of 5.74 g. (0.02 mole) of 1,3-dihydro-7- chloro-S-phenyl-ZH-1,4-benzodiazepine-2-thione and 3.6 g. (0.6 mole) of formic acid hydrazide in 200 ml. of 1- butan-ol was heated under reflux for 3 hours 45 minutes with a slow stream of nitrogen passing through the reaction mixture to remove the hydrogen sulfide formed. The reaction mixture was concentrated, and the residue was suspended in water. The solid was collected by filtration, dissolved in methylene chloride and dried over anhydrous potassium carbonate. Removal of the solvent gave a residue which was recrystallized from ethyl acetate-Skelly-solve B hexanes to give 8-chloro-6-phenyl-4H- s-triazolo[4,3-a][1,4]benzodiazepine of melting point 228229 C.

In the same manner given in Preparation 1 by heating other: 1,3-dihydro 5 phenyl-2H-1,4-benzodiazepine-2- thiones with formic acid hydrazide other 6-phenyl-4H-striazolo[4,3-a] [1,41benzodiazepines are produced. Representative compounds, thus produced, include:

8-chloro-6- 2,6-difluorophenyl) -4H-s-triazolo [4,3-

a] [1,4]benzodiazepine;

8-chloro-6- (o-chlorophenyl) -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

8-nitro-6- (o-chlorophenyl) -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

8-chloro-6- (o-fluorophenyl )-4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

6- (o-chlorophenyl) -4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

8-trifluoromethyl-6-pheny1-4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

8-nitro-6-pheny1-4H-s-triazo1o [4,3-a] 1,4] benzodiazepine;

10-ethyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4 benzodiazepine;

10-trifluoromethyl-6- [p- (dipropylamino phenyl] 4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

7-ethylthio-6- (o-bromophenyl) -4H-s-triazolo [4,3-

a] [1,4]benzodiazepine;

9-cyano-6- [p-trifluoromethyl phenyl] -4H-striazolo [4,3-a] [1,4] benzodiazepine;

7,10-dichloro-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-

a] 1,4] benzodiazepine;

4,7,9-trimethyl-6- (o-chlorophenyl) -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

10-propylsulfonyl)-6-phenyl-4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

7-dimethylamino-8-fluoro-6-phenyl-4H-s-triazolo [4, 3-

a] [1,4]benz0diazepine;

10-chloro-6- (m-isopropylphenyl -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

9- dipropylamino -6- [m- (dipropylamino) phenyl] 4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

8- (methylsulfinyl -6- (o-nitrophenyl) -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

7- (ethylsulfonyl -6- (o-cyanophenyl -4H-s-triazolo [4,3-

a] [1,4]benzodiazepine;

4-propyl-6- [m-(methylthio) phenyl]-4H-s-triazolo [4,3-

a] 1,4] benzodiazepine;

-fluoro-7-chloro-6- [p- (trifluoromethyl) phenyl] 4H-s-triazo1o [4,3-a] 1,4] benzodiazepine;

7 ,9-diethoxy-6- (m-ethoxyphenyl) -4H-s-triazolo [4,3-

a] 1,4] benzodiazepine;

4-ethyl-6- [o- (ethylthio)phenyl] -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

4-methyl-7,10-dichloro- 6- m-isoprop oxyphenyl -4H- s-triazolo [4,3-a] [1,4] benzodiazepine;

9- (dipropylam ino -6- [m- (propylthio phenyl] -4H- s-triazolo [4,3-a] 1,4] benzodiazepine;

7- (diisopropylamino -6- [p-(dipropylamino phenyl]- 4H-s-triazolo [4,3-a] 1,4] benzodiazepine;

8-chloro-6- 3,4-dimethylphenyl)-4H-s-triazolo [4,3-

a] [1,4] benzodiazepine;

6- (2-methyl-4-methoxyphenyl) -4H-s-triazolo [4,3-

a] 1,4]benzodiazepine;

S-methylthio-6-phenyl-4H-s-triazolo [4,3-a] 1,4] henzodiazepine;

8-methoxy-6-pheny1-4H-s-triazolo [4, 3 -a] 1 ,4]benzodiazepine;

and the like.

EXAMPLE 1 1, 8-dichloro- 6-phenyl-4H-s-triazo1o [4,3-a] 1,4] henzodiazepine A stirred mixture of 8-chloro-6-phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine (2.95 g., 0.01 mole) N-chlorosuccinimide (1.48 g., 0.011 mole) and carbon tetrachloride (200 ml.) was refluxed under a nitrogen atmosphere for 7 hours and kept at ambient temperature for 16 hours. Water and enough chloroform to dissolve the precipitated product were added to the mixture and the layers were separated. The aqueous layer was extracted with chloroform and the combined organic solution was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (200 g.) with 1% methanol-99% chloroform. The product obtained from the column was crystallized from ethyl acetate to give: 1,8-dichloro-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine 0.57 g., of melting point 198-199" C. and 0.19 g. of melting point 197.5-198.5 C. The analytical sample had a melting point of 198-199" C.

Analysis.Calcd. for C H Cl 'N (percent): C, 58.38; H, 3.06; CI, 21.54; N, 17.02. Found (percent): C, 58.72; H, 3.09; Cl, 21.70; N, 16.93.

EXAMPLE 2 1-bromo-8-chloro-6-phenyl-4H-s-triazo1o [4, 3- a] [1,4]benzodiazepine A stirred mixture of 8-chloro-6-phenyl-4H-s-triazolo- [4,3-a] [l,4]benzodiazepine (14.7 g., 0.05 mole), N- bromosuccinimide (8.9 g., 0.05 mole), and carbon tetrachloride (1 liter) was refluxed, under a nitrogen atmosphere for 4 hours, cooled and concentrated in vacuo. The residue was mixed with water and extracted with chloroform. The extract was dried over anhydrous potassium carbonate and concentrated. Crystallization of the residue from ethyl acetate gave 7.74 g. of 1-brorno-8-chloro-6- phenyl-4H-s-triazolo [4,3-a] [1,41benzodiazepine of melting point 202.5-206 C. The mother liquor was concentrated and chromatographed on silica gel (500 g.) with 2.5% methanol-97.5% chloroform. The product obtained from the column was recrystallized from ethyl acetate to give 3.01 g. of 1-bromo-8-chloro-6-phenyl-4H-s-triazo1o- [4,3-a][l,4]benzodiazepine of melting point 205-207". The analytical sample had a melting point of 202- 203.5 C.

Analysis.-Calcd. for C H BrClN; (percent): C, 51.43; H, 2.70; Br, 21.39; Cl, 9.49; N, 15.00. Found (percent): C, 51.32; H, 2.98; Br, 21.14; Cl, 9.59; N, 15.20.

8 EXAMPLE 3 1,8-dichloro-6- (o-chlorophenyl) -4H-s-triazolo [4,3-a] 1,4] benzodiazepine In the manner given in Example 1, 8-chloro-6-(ochlorophenyl)-4H-s-triazolo[4,3 a] [1,4]benzodiazepine was treated with N-chlorosuccinimide in chloroform to give 1,8 dichloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3 a] [1,4] benzodiazepine.

EXAMPLE 4 1,8-dichloro-6-(o-fiuoropenyl) -4H-s-triazolo [4,3-a] [1,4]benzodiazepine In the manner given in Example 1, 8-chloro-6-(o-fluorophenyl)-4Hs-triazolo[4,3 a] [1,4]benzodiazepine was treated with N-chlorosuccinimide in carbon tetrachloride to give l,8-dichloro-6-(o-fiuorophenyl)-4H-s-triazolo[4,3- a] [1,4]benzodiazepine.

EXAMPLE 5 1-bromo-6- (o-chlorophenyl)-4H-s-triazolo [4,3-a] [1,41benzodiazepine In the manner given in Example 2, 6-(o-chlorophenyl)- 4H-s-triazolo[4,3-a][1,4]benzodiazepine was treated with N-brornosuccinimide in carbon tetrachloride to give 1- 'bromo-fi-(o-chlorophenyl) 4H s triazolo[4,3-a] [1,4]

benzodiazepine.

EXAMPLE 6 1-brorno-8-chloro6- 2,6-difiuorophenyl) -4H-striazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example 2, 8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo [4,3 a] 1,4] benzodiazepine was treated with N-bromosuccinirnide in chloroform to give l-bromo 8 chloro-6-(2,6-difiuorophenyl)-4H-s-triazolo [4,3-a] 1,4] benzodiazepine.

EXAMPLE 7 7-trifluoromethy1-1,8-dibromo-6-(p-isopropyl)phenyl)- 4H-s-triazolo [4,3-a] 1,4] benzodiazepine In the manner given in Example 2, 7-trifluoromethyl- 8-bromo-6-(p-isopropylphenyl) 4H s triazolo[4,3-a] [1,4]benzodiazepine was treated with N-bromosuccinimide in chloroform to give 7-trifluoromethyl-1,8-dibromo-6-(pisopropylphenyl)-4H-s-triazolo[4,3 a] [1,4] benzodiazepine.

EXAMPLE 8 l-chloro- 1 0-dipropylamino-4-methyl- 6- (p-fluorophenyl) 4H-s-triazolo [4,3-a] [1,4] benzodiazepine 1-bromo-8,9-dicyano-4-ethyl-6- (p-nitrophenyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine In the manner given in Example 2, 8,9-dicyano-4-ethyl- 6-(p-nitrophenyl) 4H s triazolo [4,3-a][1,4-benzodiazepine was treated with N-bromoacetamide in carbontetrachloride to give l-bromo-8,9-dicyano-4-ethyl-6-(p-nitrophenyl) -4H-s-triazolo [4,3-a] 1,4] benzodiazepine.

EXAMPLE 10 1-bromo-9-ethylsulfinyl-8-fluoro-6- [m- (isopropylsulfonyl) phenyl] -4H-s-triazolo [4,3 -a] 1,4] benzodiazepine In the manner given in Example 2, 9-ethylsulfiny1-8- fluoro-6-[m-(isopropylsulfinyl)phenyl] 4H s triazolo [4,3-a][1,4]benzodiazepine was treated with N-brornosuccinimide in chloroform to give 1-bromo-9-ethylsulfinyl- 8 fluoro-6- [m- (isopropylsulfonyl) phenyl] 4H-s-triazolo- [l,4]benzodiazepine.

EXAMPLE 11 1-chloro-8-methylthio-7-nitro-6- (m-ethoxyphenyl)-4H-striazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example 1, 8-methylthio-7-nitro-6-(m-ethoxyphenyl) 4H s triazolo[4,3-a][1,4] benzodiazepine. was treated with N-chlorosuccinimide in carbon tetrachloride to give 1-chloro-8-methylthio-7-nitro- 6-(m-ethoxyphenyl)-4H-s-triazolo[4,3 a] [1,4]benzoazepine.

EXAMPLE 12 1-bromo-10ethylthio-6- (o-cyanophenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example 2, -ethylthio-6-(ocyanophenyl)-4H-s-triazolo[4,3 a][l,4]benzodiazepine Was treated with N-bromosuccinimide in chloroform to give l-bromo 10 ethylthio-6-(o-cyanophenyl)-4H-striazolo [4,3-a] [1,4]benzodiazepine.

EXAMPLE 13 8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepinel-carbonitrile A mixture of 1 bromo-8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine (7.48 g., 0.02 mole), cuprous cyanide (1.97 g., 0.022 mole) and dimethylformamide (50 ml.) was heated at 150 C., under a nitrogen atmosphere for 2 hours, cooled, poured into 25 ml. of 25% ethylenediamine and extracted with chloroform. The ex tract was washed successively with 25 ml. of 25 ethylenediamine, water and brine; dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (500 g.) with 1% methanol- 99% chloroform. The first material eluted from the column was the product which was crystallized from ethyl acetate-Skellysolve B hexanes to give 2.78 g. of 8-chloro- 6 phenyl-4H-s-triazolo[4,3 a][1,4]benzodiazepine 1- carbonitrile of melting point 193194.5. The analytical sample had a melting point of 194-195".

Analysis.Calcd. for C H ClN (percent): C, 63.85; H, 3.15; C1, 11.09; N, 21.90. Found (percent): C, 63.44; H, 3.08; Cl, 11.06; N, 21.70.

EXAMPLE 14 8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a] [1,4] benzodiazepine- 1 -carbonitrile In the manner given in Example 13, 1-bromo-8-chloro- 6-(o-chlorophenyl) 4H s triazolo[4,3-a][1,4]benzodiazepine was heated with cuprous cyanide in dimethylformamide to give 8-chloro-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-l-carbonitrile.

EXAMPLE 15 8-chloro-6- 2,6-difiuorophenyl -4H-s-triazo [4,3-a] [1,4] benzodiazepinel-carbonitrile In the manner given in Example 13, 1-br0mo-8-chloro- 6 (2,6 difluorophenyl)-4H-s-triazolo[4,3-a] [1,4]benz0- diazepine was heated with cuprous cyanide in dimethylformamide to give 8-chloro-6-(2,6-difluorophenyl)-4H-striazolo [4,3-a] [1,4] benzodiazepinel-carbonitrile.

EXAMPLE 16 6-(o-chlorophenyl) -4H-s-triazolo [4,3-a] [1,4]benzodiazepinel-carbonitrile In the manner given in Example 13, 1-brom0-6-(ochlorophenyl)-4H-s-triaz0lo [4,3 a] [1,4] benzodiazepine was heated with cuprous cyanide in dimethylformamide to give 6 (o chlorophenyl)-4H-s-triazolo[4,3-a][1,4] benzodiazepine-l-carbonitrile.

10 EXAMPLE 17 7-trifiuoromethyl-8-bromo 6 (p-isopropylphenyl)-4H-striazolo 4,3-a] [1,4] benzodiazepine- 1 -carb0nitrile In the manner given in Example 13, 1,8-dibr0mo-7-trifiuoromethyl 6 (p-isopropylphenyl)-4H-s-triazolo[4, 3-a] [1,4]benzodiazepine was heated with cuprous cyanide in dimethylformamide to give 7-trifiuoromethyl-8-bromo- 6 (p isopropylphenyl)-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-l-carbonitrile.

EXAMPLE 18 8,9-dicyano 4 ethyl-6-(pv-nitrophenyl)-4H-s-triazolo[4, 3-a] [1,4] benzodiazepine-l-carbonitrile In the manner given in Example 13, 1-bromo-8,9-dicyano 4 ethyl-6-(p-nitrophenyl)-4H-s-triazolo[4,3-a] [1,4]-benzodiazepine was heated with cuprous cyanide in dimethylformamide to give 8,9-dicyano-4-ethyl-6-(p-nitrophenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepinel -carbonitrile.

EXAMPLE 19 8-chloro-1-methoxy-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine A mixture of 1-bromo-8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine (0.374 g., 0.001 mole) was added to a solution of sodium (0.070 g.) in methanol (10 ml.); the mixture was refluxed under nitrogen for 45 minutes and poured into ice water. This mixture was extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The thusobtained residue was crystallized from ethyl acetate- Skellysolve B hexanes to give 0.21 g. of 8-chloro-1-methoxy-6-phenyl-4H-s-triazolo[4,3 a][1,4]benzodiazepine of melting point 162163 C. The analytical sample had a melting point of 163-164 C.

Analysis.-Calcd. for C H CIN O (percent): C, 62.87; H, 4.03; Cl, 10.92; N, 17.25. Found (percent): C, 62.63; H, 4.17; Cl, 10.93; N, 16.96.

EXAMPLE 20 8-chloro-1-ethoxy-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example 19, 1-bromo-8-chloro- 6 (o chlorophenyl)-4H-s-triazolo[4,3-a] [1,4]benzodiazepine was refluxed with sodium ethoxide in ethanol to give 8 chloro-l-ethoxy-6-(o-chlorophenyl)-4H-s-triazol0 [4,3-a] [1,4] benzodiazepine.

EXAMPLE 21 8-chloro-1-propoxy-6-(2,6-difluorophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example 19, 1,8-dichloro-6-(2, 6 difiuorophenyl)-4H-s-triaz01o[4,3 a] [1,4]benzodiazepine was refluxed with sodium propoxide in l-propanol to give 8 chloro-1-propoxy-6-(2,6-difluoropheny1)-4H-s-triazolo [4,3-a] [1,4]benzodiazepine.

EXAMPLE 22 1-methoxy-8-nitro-6-(o-chlorophenyl)-4H-s-triazol0 [4,3-a] [1,4]benzodiazepine In the manner given in Example 19, 1-bromo-8-nitro-6 (o-chlorophenyl) 4H s triazolo[4,3-a] [1,4]benzodiazepine was refluxed with sodium methoxide in methanol to give l-methoxy 8 nitro-6-(o-chlorophenyl)-4H-s-tri azolo[4,3-a] 1,4] benzodiazepine.

EXAMPLE 23 1-isopropoxy-6- (o-chlorophenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example 19, 1-bromo-6-(ochlorophenyl) 4H-s-triazolo[4,3-a] [1,4]benzodiazepine was refluxed with sodium isopropoxide in 2-propanol to give 1 isopropoxy-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a] [1,4] benzodiazepine.

EXAMPLE 24 7-trifluoromethyl-8-bromo 1 methoxy-6-(p-isopropylphenyl (-4H-s-triazolo [4,3-a] [1,4]benzodiazepine In the manner given in Example 19, 1,8-dibromo-7-trifluoromethyl-G- (p isopropylphenyl)-4H-s-triazolo[4,3-a] [l,4]benzodiazepine was refluxed with sodium methoxide in methanol to give 7-trifiuoromethyl-8-bromo-l-methoxy- 6 (p-isopropylphenyl)-4H-s-triazo1o[4,3 a] [l,4]benzodiazepine.

EXAMPLE 25 8,9-dicyano-4-ethyll -ethoxy-6- p-nitrophenyl) 4H-s-triazolo [4,3-a] 1,4]benzodiazepine In the manner given in Example 19, 1-bromo-8,-9-dieyano 4 ethyl-6-(p-nitrophenyl)-4H-s-triazolo[4,3-a] [l,4]benzodiazepine was refluxed with sodium ethoxide in ethanol to give 8,9-dicyano-4-ethyl-1-ethoxy-6-(p-nitrophenyl) -4H-s-triazolo [4,3-a] 1 ,4] benzodiazepine.

EXAMEPLE 26 8-chlorol-diethylamino-G-phenyl-4H-s-triazolo [4,3-a] 1,4]benzodiazepine A mixture of l-bromo-8-ch10ro-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine (7.48 g., 0.02 mole) and diethyl amine (4.5 g., 0.1 mole) with 50 ml. dimethylformamide were heated to 80 C. for 8 hours. The mixture was allowed to cool, then poured into 200 ml. of cold water and extracted with three IOU-ml. portions of chloroform. The extracts were combined, dried over anhydrous potassium carbonate, and evaporated. The thus obtained residue was crystallized from ethyl acetate-Skellysolve B hexanes to give pure 8-chloro-l-diethylamino-G-phenyl- 4H-s-triazol0 [4,3-a] [*1,4]benzodiazepine.

EXAMPLE 27 8-chloro-1-dipropylamino-6- (o-chlorophenyl) -4H-striazolo [4,3-a] [1,4] benzodiazepine 1 bromo 8-chloro-6- (o-chlorophenyl)-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine (0.002 mole) was added to a solution of 0.05 mole of dipropylamine and 0.03 mole of butyl lithium in hexamethyl phosphoric acid triamide PO[N(CH (75 ml.) and the mixture was kept at 60 C. for hours. The mixture was then poured into water and extracted with chloroform. The extracts were dried over potassium carbonate, evaporated to dryness and the resulting residue recrystallized from ethyl acetate- Skellysolve B hexanes to give 8-chloro-1-dipropylamino- 6 (o chlorophenyl) 4H-s-triazolo[4,3-a][l,4]benzodiazepine.

EXAMPLE 28 8-chloro-1-diisopropylamino-6- 2,6-difiuorophenyl 4H-s-triazolo [4,3 -a] [1,4] benzodiazepine In the manner given in Example 27, 1,8-dichloro-6-(2,6- difluorophenyl) -4H-s-triazolo[4,3-a] 1,4]benzodiazepine, diisopropylamine and butyl lithium were heated in hexarnethylphosphoric acid triamide to give S-chloro-l-diisopropylarnino 6-(2,6-difluorophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine.

EXAMPLE 29 8-chloro-l-diethylamino-6-(o-fluorophenyl -4H-striazolo [4, 3-a] 1,4] benzodiazepine In the manner given in Example 27, 1,8-dichloro-6-(ofluorophenyl) 4H-s-triazolo[4,3-a][1,4]benzodiazepine, diethylamine and butyl lithium were heated in hexamethylphosphoric acid triamide to give 8-chloro-1-diethylamino 6 (o-fluorophenyl) 4H-s-triazolo[4,3-a][1,4] benzodiazepine.

12 EXAMPLE 30 7-trifluoromethyl-8-bromo-l-diethylamino-6- (p-isopropylphenyl) -4H-s-triazolo [4,3 -a] 1,4] benzodiazepine In the manner given in Example 27, 7-trifiuoromethyl- 1,8 dibromo-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a] [l,4]benzodiazepine, diethylamine, and butyl lithium were heated in hexamethylphosphoric acid triarnide to give 7- trifluoromethyl 8-bromo-1-diethylamino-6-(p-isopropylphenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepine.

EXAMPLE 3 1 8,9-dicyano-1-dipropylamino-4-ethyl-6- (p-nitrophenyl) 4H-s-tria 2010 [4,3 -a] 1,4] benzo diazepine In the manner given in Example 27, 1-brorno-8,9-dicyano-4-ethyl 6 (p-nitrophenyl)-4H-s-triazolo[4,3-a] [1,4]benzodiazepine, dipropylamine and butyl lithium were heated in hexamethylphosphoric acid triamide to give 8,9 dicyano 1 dipropylamino-4-ethyl-6-(p-nitrophenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepine.

EXAMPLE 32 8-chlorol-dimethylamino- 6-phenyl-4I-I-s-tria zolo [4,3-a] [1,4] benzodiazepine 8 chloro 1 bromo 6-phenyl-4I-I-s-triazolo[4,3-a] [1,4]benzodiazepine was dispersed in dimethylformamide saturated with dimethylamine. The mixture was introduced into a heavy gauge tube, the tube sealed and heated for 14 hours at 65 C. After cooling, the tube was opened, the reaction mass was poured into water and the miixture extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, evaporated and the resulting residue recrystallized from ethyl acetate to give pure 8 chlorol-dimethylamiuo-6-phenyl-4H-s-triazolo[4,3-a] [1,4] benzodiazepine.

EXAMPLE 33 8-chloro-6-phenyl- 1-pyrrolidino-4H-s-triazolo [4,3 -a] [l,4]benzodiazepine A stirred mixture of 1 bromo 8 chloro 6 phenyl- 4H-s-triazolo[4,3-a] [1,4] benzodiazepine (0.374 g.=0.001 mole in 2.5 ml. of pyrrolidine was refluxed for 5 hours under nitrogen. The resulting solution was allowed to remain for 18 hours at room temperature and then poured into ice water. The resulting solids were collected by filtration, washed with water and dried in vacuo to give 0.277 g. of crude product. This product combined with an extract (chloroform) obtained from extracting the filtrate was suspended in dilute base and then extracted with methylene chloride. This extract was washed with aqueous brine, dried over anhydrous potassium carbonate and concentrated in vacuo to give a residue. This residue was redissolved in toluene and again concentrated in vacuo to give a residue which was crystallized from methanolmethylene chloride to give 0.051 g. of a by-product.

The mother liquor was concentrated, the resulting residue was redissolved and decolorized with activated charcoal (Darco Co-60) concentrated again and the residue therefrom recrystallized from ethyl acetate-Skellysolve B hexanes to give 0.1629 g. of 8-chloro-6-phenyl-1-pyrrolidino-4H-s triazol0[4,3-a] [1,4]benzodiazepine of melting point 184.5185.5 C.

Analysis.Calcd. C H CIN (percent): C, 66.02; H, 4.99; N, 19.25; Cl, 4.75. Found (percent): C, 65.46; H, 4.95; N, 19.31; Cl, 9.68.

Using in Example 33 piperidine or morpholine instead of pyrrolidine gives 8-chloro-6-phenyl-l-piperidino-4H-striazolo[4,3-a] [1,4]benzodiazepine and respectively 8- chloro 6 phenyl l morpholino 4H-s-triazolo[4,3-a] [1,4] benzodiazepine.

In the manner given in the preceding examples, other 1 substituted 6 phenyl 4H s triazolo[4,3-a] [1,4]

benzodiazepines of Formula VI can be prepared. Representative compounds, thus prepared, include:

9-(diproylamino)-1-chloro-6- [p-(dipropylamino)phenyl] -4H-s-triazolo[4,3-a] [1,4] benzodiazepine;

8- methylsulfinyl -1-bromo-6-( o-nitrophenyl -4H-striazolo[4,3-a] [1,4]benzodiazepine;

7- ethylsulfonyl -6 (o-cyanophenyl -4H-s-triazolo [4,3-

a] [1,4] benzodiazepine-l-carbonitrile;

4-propyl-1-methoXy-6-[m-(methylthio )phenyl] -4H-striazolo [4,3-a] [1,4]benzodiazepine;

1 O-fiuoro-7-chloro-1-diethylamino-6- [p- (trifiuoromethyl) phenyl]-4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

7,9-diethoxy-1-bromo-6-(m-ethoxyphenyl)-4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

4-ethyl- 1-methoxy-6- (ethylthio phenyl] -4H-s-triazolo [4,3-a] 1,4]benzodiazepine;

4-methyl-7,10-dichloro-1-ethoXy-6-(m-isopropoxyphenyl -4H-s-triazolo [4,3-a] 1,4] benzodiazepine;

9-(dipropy1amino)-1-chloro-6-[m-(propylthio)phenyl]- 4H-s-triazo1o [4,3-a] [1,4] benzodiazepine;

7- (diisopropylamino -1-bromo-6- [pdipropylamino) phenyl] -4H-s-triazolo [4,3-a] 1,4]benzodiazepine;

4-isopropyl-7,9-difluoro-1-morpholino-6-phenyl-4H-striazolo [4,3-a] [1,4]benzodiazepine;

8-chlorol-piperidino- 6- (3 ,4-dimethylphenyl-4H-s-triazolo[4,3-a] [1,4] benzodiazepine;

6- 2-methy1-4-methoxyphenyl -4H-s-triazolo [4,3-a] [1,4]

benzodiazepinel-carbonitrile;

8-methylthio-1-methoxy-6-phenyl-4H-s-triazolo[4,3-a] [1,

4] benzodiazepine;

8-rnethoxy-1-ethoxy-6-phenyl-4H-s-triazolo [4,3-a] 1,4]

benzodiazepine;

1,10-dich1oro-6-(m-isopropylphenyl)-4H-s-triazolo [4,3-a] [1,41benzodiazepine;

9- (dipropylamino 1-bromo-6-[p-(dipropylamino phenyl] -4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

8-methy1sulfiny1) -1-bromo-6 (o-nitrophenyl)-4H-striazolo[4,3-a] [1,4]benzodiazepine;

7- (ethylsulfonyl) -1-propyloxy-6- o-cyanophenyl -4H- s-triazolo [4,3-a] 1,4] benzodiazepine;

4-propyl-1-isopropyloxy-6- [mmethylthio )phenyl] -4H- s-triazolo[4,3-a] [1,4] benzodiazepine;

10-fiuoro-7-chloro-1-ethoxy-6-[p- (trifiuoromethyl)phenyl] -4H-s-triazolo[4,3-a] [1,4] benzodiazepine; I

7,9-diethoxy-6- (m-ethoxyphenyl) -4H-s-triazolo [4,3-a]

[1,4] benzodiazepine-l-carbonitrile;

7- propylthio) -6- (m-iodophenyl -4H-s-triazolo [4,3 -a] [1,4] benzodiazepine-l -carbonitrile;

1-chlor0-4-ethyl-6- [o- (ethylthio phenyl] -4H-s-triazolo [4,3-a] [1,4]ben2odiazepine;

7,10dichloro-1-ethoxy-4-methyl-6-(m-isopropoxyphenyl)-4H-s-triazolo [4,3-a] [1,4benzodiazepine;

9- (dipropylamino) -1-propoxy-6-[m-(propylthio) phenyl] 4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

7- diisopropylamino -1-chloro-6- [p- (dipropylamino) phenyl)-4H-s-triazolo 4, 3 -a] 1,4] benzodiazepine;

8-chloro-6- 3 ,4-dimethylphenyl -4H-s-triazolo [4,3-a]

[ 1,4] benzodiazepinel-carbonitrile;

6- 2-methyl-4-methoxyphenyl -4H-s-triazolo [4,3 -a] [1,4] benzodiazepinel-carbonitrile;

8-methylthio-1-bromo-6-phenyl-4H-s-triazolo [4,3-a]

[1,4] benzodiazepine;

8-methoxy-1-eh1oro-6-phenyl-4H-s-tri-azolo [4, 3 -a] 1,4]

benzodiazepine;

8-chloro-1-pyrrolidino-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

8-chloro-1-morpholino-6- (o-nitrophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

8-chloro-1-piperidino-6-(2,6-difluorophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

and the like.

14 What is claimed is 1. A compound of the formula wherein R is selected from the group consisting of chlorine, bromine, cyano, OR in which R is an alkyl group of 1 to 3 carbon atoms, inclusive, and

in which R and R' are alkyl groups, defined as above, or together represent pyrrolidino, piperidino, and morpholino; wherein R is selected from the group consisting of hydrogen and alkyl, as defined above; and wherein R R R and R are selected from the group consisting of hydrogen, and alkyl, as defined above, fluoro, chloro, bromo, nitro, cyano, trifiuoromethyl, and alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive,

wherein R is X in which X is chlorine or bromine; wherein R is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, inclusive; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl as defined above, fluoro, chloro, bromo, nitro, cyano, trifiuoromethyl, and alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive.

3. The compound of claim 2 wherein X is bromine, R R R and R are hydrogen, R is 8-chloro, and the compound is therefore 1-bromo-8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine.

4. The compound of claim 2 wherein X is chlorine, R R R and R are hydrogen, R is 8-chloro and the compound is therefore 1,8-dichloro-6-phenyl-4H-s-triazolo [4,3-a] 1,4]benzodiazepine.

5. A compound according to claim 1 wherein R is cyano.

6. The compound according to claim 1 wherein R is cyano, R R R and R are hydrogen, R is S-chloro and the compound is therefore 1-cyano-8-chloro-6phenyl- 4I-I-s-triazolo [4,3-a] [1,4-]benzodiazepine.

7. A compound according to claim 1 wherein R is OR in which R is an alkyl of 1 to 3 carbon atoms, inclusive.

8. The compound according to claim 1 wherein R is OR in which R is methyl, R R R and R are hydrogen, R is 8-chloro and the compound is therefore l-methoxy- 8 chloro-6-phenyl-4fi-s triazolo [4,3 a] [1,4] benzodiazepine.

9. The compound according to claim 1 wherein R is OR in which R is ethyl, R R R and R are hydrogen, R is 8-chloro and the compound is therefore l-ethoxy-8-chloro-6-phenyl-4H-s-triazolo[4,3 a] [1,41benzodiazepine.

10. A compound according to claim 1, wherein R is in which R and R" are alkyl of 1 to 3 carbon atoms, inclusive. 11. The compound according to claim 1 wherein R 18 in which R and R" are methyl R R R and R are hydrogen, R is 8-chloro and the compound is therefore l-dimethylamino-8-ch1oro-6-phenyl-4H-s triazolo[4,3 a]

[ 1,4]benzodiazepine.

12. The compound according to claim 1 wherein R is N R5 R4 wherein X is chlorine or bromine; where R, is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, inclusive; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl as defined above, fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyL-and alkylsulfonyl, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, which comprises: Heating between 40-76 C. a 6-phenyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine (I) N H--( M 7 u RS\/ ill c Ra

which comprises: heating bet-ween 4076 C. a 6-phenyl- 4H-s-triazolo1j4,3-a] [1,41benzodiazepine (I) wherein R R R R and R are selected from the group consisting of hydrogen, alkyl as defined above, fluoro, chloro, bromo, nitro, cyano, trifiuoromethyl, and alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of l to 3 carbon atoms, inclusive, with a N-brornosuccinimide in an inert, organic solvent, to give the corresponding 1-bromo-6- phenyl-4H s triazolo[4,3-a] [1,41benzodiazepine (Ila); and heating IIa 'with cuprous cyanide in an inert, organic, high boiling solvent to -170 to obtain the corresponding 1-cyano-6-phenyl 4H s triazolo[4,3-a] [1,4] benzodiazepine (III) of above.

16. A process for the production of a compound of Formula IV:

1 7 prises: heating at 40-7 6 C. a 6-phenyl-4H-s-triazol0[4,3- a] [1,4]benzodiazepine (I) wherein R R R R and R are defined as above, with a N-chloroor N-bromosuccinimide in an inert, organic solvent, to give the corresponding l-chloroor 1-bromo-6-pheny1 4H s triazolo [4(3 a] [1,4]benzodiazepine (II); and heating II at 60-97" C. with sodium or potassium lower alkoxide, in which the alkoxy group has the formula RO in which R is alkyl of 1 to 3 carbon atoms, inclusive, in an excess of a lower alkanol R'OH in which R is defined as above, to obtain the corresponding 1-alkoxy-6-phenyl-4H s triazo1o[4,3-a] [1,4] benzodiazepine (IV), as above.

17. A process for the production of a compound of the Formula V RI! N N N 4 N R5 wherein R" and R'" are alkyl of 1 to 3 carbon atoms, inclusive, or together RIII represents pyrrolidino, piperidino, and morpholino; wherein R is selected from the group consisting of hydrogen and alkyl, as defined above; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl as defined above, fluoro, chloro, bromo, nitro, cyano, triflnoromethyl, and alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, which com- 18 prises: heating at 40-76 C. a 6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine (I) wherein R R R R and R are defined as above, with a N-chloroor N-bromosuccinimide in an inert, organic solvent, to give the cor-responding l-chloroor 1- bromo-6-phenyl-4H s triazolo[4,3-a] [1,4]benzodiazepine (II), and heating II to 100 C. with a dialkylamine of the formula in which R" and R' are alkyl of one to three carbon atoms, inclusive, or together UNITED STATES PATENTS 3,646,055 2/1972 Hester 260308 C FOREIGN PATENTS 6,916,543 5/1970 Netherlands 260308 R 2,012,190 9/1970 Germany 260308R ALTON D. ROLLINS, Primary Examiner US. Cl. X.R. 

